slide1 l.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Continuing Reassessment of the Risks of Erythropoiesis-Stimulating Agents (ESAs) in Patients with Cancer PowerPoint Presentation
Download Presentation
Continuing Reassessment of the Risks of Erythropoiesis-Stimulating Agents (ESAs) in Patients with Cancer

Loading in 2 Seconds...

play fullscreen
1 / 84

Continuing Reassessment of the Risks of Erythropoiesis-Stimulating Agents (ESAs) in Patients with Cancer - PowerPoint PPT Presentation


  • 312 Views
  • Uploaded on

Continuing Reassessment of the Risks of Erythropoiesis-Stimulating Agents (ESAs) in Patients with Cancer . Vinni Juneja, MD Division of Biologic Oncology Products. Oncologic Drugs Advisory Committee May 10, 2007. Credits. Chaohong Fan Patricia Keegan Mark Rothmann Yuan Li Shen

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Continuing Reassessment of the Risks of Erythropoiesis-Stimulating Agents (ESAs) in Patients with Cancer' - lotus


Download Now An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
slide1

Continuing Reassessment of the Risks of Erythropoiesis-Stimulating Agents (ESAs) in Patients with Cancer

Vinni Juneja, MD

Division of Biologic Oncology Products

Oncologic Drugs Advisory Committee

May 10, 2007

credits
Credits
  • Chaohong Fan
  • Patricia Keegan
  • Mark Rothmann
  • Yuan Li Shen
  • Kyung Lee
  • Monica Hughes
outline
Outline
  • Introduction
  • Regulatory History
  • Benefits vs Risks of ESAs
  • Safety signals leading to ODAC May 2004
  • ODAC 2004
  • Data from Recent Trials since ODAC 2004
  • “Meta Analyses” considerations
continuing assessment of esa risks vs benefits
Continuing assessment of ESA risks vs benefits

Risks of ESAs in Cancer Patients

  • Decreased Survival
  • Tumor Promotion
    • Decreased locoregional control
    • Decreased progression free survival?
  • Increased thrombovascular events (TVEs)
esas for chemotherapy associated anemia
ESAs for Chemotherapy-associated Anemia

Epoetin alfa and beta have same amino acid sequence but differ in glycosylation

class effect of esas
Class Effect of ESAs
  • FDA considers all ESAs as members of the same product class
  • Risks of ESAs apply to all products
outline7
Outline
  • Introduction
  • Regulatory History
  • Benefits vs Risks of ESAs
  • Safety signals leading to ODAC May 2004
  • ODAC 2004
  • Data from Recent Trials since ODAC 2004
  • “Meta Analyses” considerations
procrit epogen epoetin alfa
Procrit/Epogen(epoetin alfa)
  • Epoetin alfa products licensed in the U.S. are manufactured by Amgen
    • EPOGEN distributed by Amgen → Dialysis pts
    • PROCRIT distributed by Ortho Biotech (subsidiary of J&J) → all other indications
  • EPOGEN and PROCRIT labeling is identical
procrit epogen epoetin alfa9
Procrit/Epogen(epoetin alfa)
  • Non-cancer Approvals
    • 1988-anemia of Chronic Renal Failure
    • 1991-AZT related anemia in AIDS
    • 1995-reduction of perioperative transfusion
  • Cancer Approvals
    • 1993-Anemia associated with chemo
    • June 2004-Weekly dosing in Anemia with chemo
  • Revisions to Label
    • May 2004-Effects on RR, TTP, and OS in solid tumors
approval of procrit epogen 1993
Approval of Procrit/Epogen: 1993
  • Approved for cancer patients on chemotherapy based on reduction in % pts transfused
  • Infectious risks of blood transfusion in 1993 higher than in 2007
  • Pooled data from 6 randomized, double blind, placebo controlled trials in a total of 131 patients, with different malignancies was basis for approval.
  • Theoretical potential for tumor promotion based on EPO receptor expression in tumors/vasculature unresolved
  • Post Marketing Commitment to address impact of Procrit on tumor response and survival
aranesp darbepoetin alfa
Aranesp(darbepoetin alfa)
  • First approval in 2001 for anemia of CRF
    • Subsequent approvals in cancer patients:
      • July 2002- Anemia associated with cancer chemotherapy, weekly dosing
      • March 2006- Every 3 week dosing for anemia associated with cancer chemotherapy
approval of aranesp 2002 study 980297
Approval of Aranesp: 2002Study 980297
  • Approved for cancer patients on chemotherapy based on reduction in % pts transfused
  • Approval based on data from Study 980297, a randomized, double blind, placebo controlled trial (N=314)
  • Patient Population: Lung CA (NSCLC + SCLC)
  • No difference in PFS or OS
    • Limitation: Study not sized to detect small but clinically meaningful differences in PFS and OS.
current label
Current Label
  • The dose of ESAs should be titrated for each patient to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for blood transfusion and not to exceed 12 g/dL
current label14
Current Label
  • ESAs are indicated for treatment of anemia in pts w/non-myeloid malignancies where anemia is due to effect of concomitantly administered chemo
  • ESAs are indicated to decrease need for transfusions in patients who will be receiving concomitant chemo for a minimum of 2 months
  • ESAs are not indicated for the treatment of anemia in cancer patients due to other factors such as iron/folate deficiencies, hemolysis, or GI bleeding, which should be managed appropriately
outline15
Outline
  • Introduction
  • Regulatory History
  • Benefits vs Risks of ESAs
  • Safety signals leading to ODAC May 2004
  • ODAC 2004
  • Data from Recent Trials since ODAC 2004
  • “Meta Analyses” considerations
benefits of esas
Benefits of ESAs
  • Clinical benefits of ESAs were demonstrated in anemic pts receiving chemo who were able to avoid RBC transfusions & their concomitant risks
  • Use of ESAs reduced proportion of pts receiving RBC transfusions & their concomitant risks
benefits of esas17
Benefits of ESAs

Procrit 1993 Approval

Aranesp 2002 Approval

current practices for esas vs rbc transfusion
Current Practices for ESAs vs RBC Transfusion
  • ESAs
    • Initiated when pt anemic
    • Reimbursement for ESAs begin when Hgb<12.0
  • RBC Transfusion
    • Recommended when Hgb 7-8, or as clinically necessary
  • Because benefit of ESA is avoidance of transfusion, should ESAs be initiated at or titrated to achieve a lower Hgb?
transfusion medicine
Transfusion Medicine
  • RBC transfusion rarely given when Hgb >10
  • Body can compensate for chronic anemia by:
    • ↑ DPG
      • shift of O2 dissociation curve→ ↑ release of O2 to body tissues
    • ↑ peripheral vasodilation
    • ↑ cardiac output
      • Usually does not increase until Hgb < 7
  • Symptoms due to chronic anemia may not appear until Hgb < 7-8
rbc transfusions risks
RBC Transfusions Risks

Procrit Approval

Blajchman et al 2006

slide21

Current RBC Transfusion Risks (per RBC unit)

1 in 10,000

1 in 10 million

1 in 100

1 in 100 million

1 in 100,000

1 in 1,000,000

1 in 1000

1 in 10

1 in 1

HIV

HCV

HBV

Bacterial Infection

Fatal Bacteremia

Mistransfusion

TRALI

TA-GVHD

effects of esas
Effects of ESAs
  • Improved QOL, fatigue, and other symptoms associated with anemia NOT established in properly conducted, randomized, double-blind, placebo-controlled trials.
  • Improved survival or improved tumor control NOT established
risks of esas
Risks of ESAs
  • Increased thrombovascular events (TVEs)
    • Increased Morbidity, Potential Increased Mortality
  • Decreased Survival
  • Increased Tumor Promotion
    • Decreased Locoregional Control
    • Decreased Progression-Free Survival?
risks of esas24
Risks of ESAs
  • 5 studies w/evidence of ↑ tumor promotion or ↓ survival with excessive target Hgb
    • BEST (Breast)*
    • ENHANCE (Head/Neck)
    • DAHANCA (Head/Neck)
    • 161 (Lymphoid Ca)*
    • CAN-20 (NSCLC)
  • 1 study w/evidence of ↓ survival with target Hgb consistent w/prior label (<13 g/dL)
    • 103 (Anemia of Cancer) (Many tumor types)

* = pts receiving chemo

outline25
Outline
  • Introduction
  • Regulatory History
  • Benefits vs Risks of ESAs
  • Safety signals leading to ODAC May 2004
  • ODAC 2004
  • Data from Recent Trials since ODAC 2004
  • “Meta Analyses” considerations
slide26

GBR-7 (H/N)

RTOG 9903 (H/N)

GER-22 (NSCLC)

CAN-20 (NSCLC)

CAN-17 (Breast)

AGO (Cervical)

BEST

(Breast)

Epoetin alfa Studies

ODAC 2004

N93-004

(SCLC)

EPO-ANE-3010

(Breast)

Other Amgen Studies

2001-0145 (SCLC)

PREPARE (Breast)

ARA-03 (Breast)

DAHANCA (H/N)

GELA (NHL)

ENHANCE

(Head/Neck)

Aranesp Studies

Anemia of Cancer (103)

Lymphoid Ca (161)

Non-Myeloid (232)

trial design considerations
Trial Design Considerations
  • Superiority trial purpose: show improved outcome (i.e. improved OS, PFS, or RR) for ESA
    • Hypothesis: ↑ Hgb=improved outcome
    • Failure to show superior survival with ESAs does NOT exclude the possibility of ↓ survival.
  • Non Inferiority trial purpose: exclude ↑ risk
    • 2 trials w/ESAs in cancer pts were specifically designed to detect unacceptable risk
    • Non-inferiority design preferable to exclude ↑ risk
slide28

ESA Non Inferiority Studies

Epoetin alfa Studies

ODAC 2004

N93-004

(SCLC)

EPO-ANE-3010

(Breast)

Other Studies

Aranesp Studies

primary data vs summary result
Primary Data vs Summary Result
  • Primary Data: database from clinical trial with efficacy data (i.e. OS, RR), safety data (i.e. TVE), & all data captured on CRFs submitted to FDA
    • FDA independently analyzes database/verifies result
  • Summary Result: descriptive data analyzed by investigators submitted to FDA
    • Examples: journal abstract/ publication/ report
    • FDA cannot perform independent analysis & cannot verify results
    • FDA cannot detect flaws in data
slide30

Studies w/Primary Data Submitted to FDA

Epoetin alfa Studies

BEST

(Breast)

ODAC 2004

N93-004

(SCLC)

Other Studies

Aranesp Studies

slide31

Data Leading to ODAC 2004

Epoetin alfa Studies

BEST(Breast)

ODAC 2004

N93-004

(SCLC)

Other Studies

ENHANCE(Head/Neck)

Aranesp Studies

odac may 2004
ODAC May 2004
  • ODAC convened after FDA received 1° data from N93-004, and ↑ mortality in BEST + ENHANCE
  • NSCLC trial (CAN-20) terminated early due to ↑ TVEs in other trials & ↑ mortality in BEST + ENHANCE
    • Unplanned analysis suggested ↑ mortality in ESA arm
  • Head & Neck cancer trial (RTOG 9903) terminated early due to publication of ENHANCE trial in 2003
    • Unplanned analysis demonstrated non-significant trend to ↓ loco-regional control & ↑ mortality in ESA arm
  • 4 other randomized controlled trials terminated early due to ↑ TVEs
slide33

N93-004 (SCLC)

Epoetin alfa Studies

ODAC 2004

N93-004

(SCLC)

Other Studies

Aranesp Studies

study n93 004 sclc
Study N93-004 (SCLC)

1° Endpoint: ORR

Cisplatin/Etoposide/RT

Procrit

Limited/Extensive Stage SCLC

N=224

2° Endpoint: OS

Cisplatin/Etoposide/RT

Placebo

Target Hgb 14-16

  • PMC for 1993 approval of Procrit
  • Non-inferiority study on ORR
  • Intended to enroll 400 patients
  • Study terminated for poor accrual at 224 patients

ORR=CR+PR

study n93 004 sclc35
Study N93-004 (SCLC)
  • ORR was determined w/o central review of images
  • 17% of patients had missing tumor response data
  • Confirming ORR by repeat imaging was not required
  • ORR not a sensitive detection method for tumor promotion
slide36

BEST(Breast)

Epoetin alfa Studies

BEST (Breast)

ODAC 2004

Other Studies

Aranesp Studies

best breast
BEST (Breast)

1° Endpoint: 12 mo OS

Chemo

Eprex

Stage 4 Breast Cancer

N=939

2° Endpoint: ORR, TTP

Chemo

Placebo

Target Hgb 12-14

  • Superiority Trial on 12 month OS
  • Stratified by site of metastases

TTP: Time to Progression

ORR=CR+PR

best breast38
BEST (Breast)
  • Increased Mortality & Shorter TTP evident in 1st 4 months
  • Inadequate tumor assessments at baseline
    • 26% of placebo subjects; 29% of Eprex subjects
  • Incomplete tumor assessments throughout study
    • 28% of all patients
  • No reported set schedule for objective tumor assessment
  • Incomplete assessment of all known metastatic lesions
slide39

ENHANCE (Head/Neck)Henke et al

Epoetin alfa Studies

ODAC 2004

Other Studies

ENHANCE(Head/Neck)

Aranesp Studies

enhance head neck henke et al
ENHANCE (Head/Neck) Henke et al

1° Endpoint: LR PFS

Adjuvant or Definitive RT

Epoetin Beta

Head/Neck Cancer (T3, T4, or node +)N=351

2° Endpoint: OS, LRC

Adjuvant or Definitive RT

Placebo

Target Hgb 14-15

  • Superiority Trial on LR PFS
  • Stratified by resection status

LR PFS: Locoregional Progression Free Survival

LRC: Locoregional control

enhance head neck henke et al41
ENHANCE (Head/Neck) Henke et al

N=351, Intent to treat population

Epoetin beta demonstrated a detrimental effect on all 3 endpoints

LR PFS: Locoregional Progression Free Survival

LRC: Locoregional control

summary of pre odac 2004 trials
Summary of Pre ODAC 2004 Trials
  • N93-004 (SCLC): met its non-inferiority endpoint, ORR
  • BEST (Stg IV Breast Ca): ↓ survival for pts on ESA arm
  • ENHANCE (Head/Neck Ca): ↓ survival & ↓ locoregional control for pts on ESA arm
outline43
Outline
  • Introduction
  • Regulatory History
  • Benefits vs Risks of ESAs
  • Safety signals leading to ODAC May 2004
  • ODAC 2004
  • Data from Recent Trials since ODAC 2004
  • “Meta Analyses” considerations
slide44

ODAC 2004 Recommendations

Epoetin alfa Studies

BEST(Breast)

ODAC 2004

N93-004

(SCLC)

Other Studies

ENHANCE(Head/Neck)

Aranesp Studies

odac 2004 recommendations
ODAC 2004 Recommendations
  • Double Blind, Placebo-Controlled Trials
  • Preferred Primary Endpoint: Survival
  • Adequately powered trials to detect survival differences
  • Routine Assessment of Tumor Progression
  • Homogeneous Tumor Type
  • Tumor biopsies to assess for EPO receptors was optional
  • Studies conducted outside of US would be generalizable to the US cancer population
  • Assessment of TVEs should be prospectively defined endpoint.
    • Case report forms should be designed to capture clinically symptomatic TVEs.
    • TVEs should be assessed at prespecified intervals.
outline46
Outline
  • Introduction
  • Regulatory History
  • Benefits vs Risks of ESAs
  • Safety signals leading to ODAC May 2004
  • ODAC 2004
  • Data from Recent Trials since ODAC 2004
  • “Meta Analyses” considerations
slide47

ODAC 2004: Trials to Assess Risk

GBR-7 (H/N)

RTOG 9903 (H/N)

GER-22 (NSCLC)

CAN-20 (NSCLC)

CAN-17 (Breast)

AGO (Cervical)

Epoetin alfa Studies

ODAC 2004

EPO-ANE-3010

(Breast)

Other Amgen Studies

2001-0145 (SCLC)

PREPARE (Breast)

ARA-03 (Breast)

DAHANCA (H/N)

GELA (NHL)

Aranesp Studies

odac 2004 trials to assess risk
ODAC 2004: Trials to Assess Risk
  • Have any ongoing or proposed trials presented at ODAC 2004 or since ODAC 2004 fully met ODAC’s recommendations?

NO

  • 2 trials have come close
    • Amgen SCLC (2001-0145)
    • J&J Breast Ca (EPO-ANE-3010)
  • Other trial designs have not met several of ODAC recommendations
slide49

“Adequately” Designed Trials

Epoetin alfa Studies

ODAC 2004

EPO-ANE-3010

(Breast)

Other Studies

Aranesp Studies

amgen sclc 2001 0145
Amgen SCLC (2001-0145)

1° Endpoints: Survival ∆Hgb

Platinum/Etoposide

Aranesp

Extensive Stage SCLC

N=596

Target Hgb 13-14

Platinum/Etoposide

Placebo

  • Superiority Trial on co-primary endpoints, OS & ∆Hgb
  • Pts on 1st line chemo
  • Trial design presented at ODAC 2004
  • Accrual from December 2002 to July 2006
amgen sclc 2001 014551
Amgen SCLC (2001-0145)
  • Results (summary result April 2007)
    • Failed to demonstrate superior OS
    • OS- HR 0.93, 95% CI 0.78, 1.11
    • ↑ TVE for Aranesp arm (12.3% vs 7.4%)
  • Limitation
    • SCLC results unlikely to be generalizable to other tumor types
j j breast cancer epo ane 3010
J&J Breast Cancer (EPO-ANE-3010)

1° Endpoint: PFS

Chemotherapy

Eprex

Stage IV Breast Ca

N=108 of 1000

2° Endpoint: ORR, TTP, OS, TVEs, Response Duration

Chemotherapy

Transfusion Support

Target Hgb 12

  • Non-inferiority trial on PFS
  • Stage IV Breast Ca receiving a variety of 1st line metastatic chemo regimens
  • Design presented at ODAC May 2004
  • Final protocol submitted to FDA in December 2004
  • Accrual began March 2006, and is currently ongoing
j j breast cancer epo ane 301053
J&J Breast Cancer (EPO-ANE-3010)
  • Limitations
    • Target accrual 2000 pts (ODAC 04)→1000 pts now
      • 2000 pts: 80% power to exclude a 15% reduction in PFS
      • 1000 pts: 90% power to exclude a 25% reduction in PFS
    • Heterogeneity of chemotherapy
    • Open Label
  • Accrual has been slow
    • Final protocol submitted December 2004
    • Enrollment began March 2006, and 108 pts of target 1000 accrued as of March 2007
slide54

Studies with ↓ Survival or ↑ Tumor Promotion

CAN-20 (NSCLC)

Epoetin alfa Studies

BEST

(Breast)

ODAC 2004

Other Studies

ENHANCE

(Head/Neck)

DAHANCA (H/N)

Aranesp Studies

Anemia of Cancer (103)

Lymphoid Ca (161)

anemia of cancer 2001 0103
Anemia of Cancer (2001-0103)

1° Endpoint: % transfusion

Aranesp

Non Myeloid Ca (not on chemo or myelosuppressive RT)

N=989

2° Endpoint: OS

Placebo

Target Hgb: 12-13

  • Pts could not receive myelosuppressive Rx
  • Stratified by tumor/Rx (CLL/indolent NHL, hormonal/antibody Rx, vs all other pts)
  • Accrual April 2004 – May 2006
  • Summary of results December 2006
  • Primary Data submitted to FDA March 2007
anemia of cancer 2001 010356
Anemia of Cancer (2001-0103)
  • Results (FDA review of primary data)
    • Shorter OS (HR 1.30; [95% CI: 1.07, 1.57], p=0.008) in Aranesp arm
    • No statistically significant reduction in % patients receiving RBC transfusions in Aranesp arm
    • Increased TVEs, 3.1% vs 1.3%, in Aranesp arm
  • Indication in Rx of “Anemia of Cancer” (i.e. for cancer pts not on chemo) existed only outside US
  • Following results of Anemia of Cancer study, J&J removed the “Anemia of Cancer” indication
lymphoid ca 2000 0161
Lymphoid Ca (2000-0161)

Chemo

Aranesp

1° Endpoint: Hgb response

Lymphoid Ca (MM, NHL, WM, HD, CLL)

N=344

Chemo

Placebo

Target Hgb: 13-15 M, 13-14 F

  • Stratified by Tumor Type and Prior chemo
  • Accrual November 2000 – November 2001
  • Results presented by Amgen ODAC 2004
  • Updated Primary Data submitted April 2007
lymphoid ca 2000 016158
Lymphoid Ca (2000-0161)
  • Results (FDA review of updated primary data)
    • Shorter OS (HR 1.37 [95% CI 1.02, 1.83], p=0.037) in Aranesp arm
    • Increased TVE Grade 3-5 (3.4% vs 0.6%) in Aranesp arm
dahanca head neck
DAHANCA Head/Neck

1° Endpoint: LRC

Definitive RT

Aranesp

Head/Neck Cancer (T1-T4)

N=522

2° Endpoint: OS, LC, DSS

Definitive RT

Transfusion Support

Target Hgb 14.0-15.5

  • Superiority trial for LRC
  • Trial presented at ODAC 2004
  • Accrual July 2002 - October 2006
  • Terminated early based on interim analysis

LRC: Locoregional control LC: Local Control DSS: Disease Specific Survival

Study SE 2002-9001

dahanca head neck60
DAHANCA Head/Neck
  • Result summary provided by DAHANCA
    • Locoregional Control: worse in Aranesp arm (p=0.01)
    • OS: shorter survival in Aranesp arm (p=0.08)

Study SE 2002-9001

epo can 20 nsclc
EPO-CAN-20 NSCLC

Eprex

NSCLC, palliative care (Stage IIIA/IIIB/IV or recurrent)

N=70

1° Endpoint: QOL

Target Hgb: 12-14

Transfusion Support

  • Superiority trial on QOL
  • Trial presented at ODAC 2004
  • Accrual February 2001-November 2003
  • Terminated early; Unplanned analysis = ↑ mortality in ESA arm (Target accrual=300)
epo can 20 nsclc62
EPO-CAN-20 NSCLC
  • Results (JCO March 2007)
    • Shorter survival in Eprex arm (HR 1.84; [95% CI, 1.01, 3.35], p= 0.04)
    • TVE incidence not reported
summary of post odac 2004 trials with survival or tumor promotion
Summary of Post ODAC 2004 Trials with ↓ Survival or ↑ Tumor Promotion
  • Anemia of Cancer (variety of tumors)
    • ↓ OS with ESA(HR 1.30; [95% CI: 1.07, 1.57])
  • Lymphoid Ca (variety of Lymphoid Ca)
    • ↓ OS with ESA(HR 1.37 [95% CI 1.02, 1.83])
  • DAHANCA (Head/Neck Ca)
    • ↓ Locoregional control with ESA(p=0.01)*
    • Trend to ↓ OS with ESA(p=0.08)*
  • EPO-CAN-20 (NSCLC)
    • ↓ OS with ESA(HR 1.84; [95% CI, 1.01, 3.35])

*=nominal p value

studies without reported safety signal
Studies without Reported Safety Signal
  • 9 completed/ongoing studies: no safety signals but have significant design limitations
  • 1/9 studies: Primary data submitted to FDA
  • 1/9 studies: Primary data submitted but data not analyzable
  • 7/9 studies: Summary results only
slide65

Studies without a Reported Safety Signal that have Significant Limitations

Epoetin alfa Studies

ODAC 2004

Other Studies

Aranesp Studies

limitations
Limitations
  • Limitations to detect safety signals
    • Inadequate frequency/modality of radiological assessments to evaluate tumor recurrence
    • Inadequate radiological assessments to rule out distant metastases at baseline/during surveillance
    • No systematic TVE assessment
    • Open Label
    • Target Hgb not consistent w/current recommendations
    • Off Label ESA dosage & dose adjustments
  • Primary data not submitted to FDA on trials that have finished enrollment (except 232)
specific limitations
Specific Limitations
  • Heterogeneous tumor type
    • 232
  • Survival data limited to 5 months follow up
    • 232
  • Use of ESA in control group
    • GELA DLBCL
ongoing studies
Ongoing Studies
  • 3 of 12 studies ongoing/proposed at ODAC 2004 as capable of addressing safety concerns of ESAs continue to accrue pts
  • Only 1 of these studies, EPO-ANE-3010 is “adequately” designed, but has significant difficulties accruing pts
slide69

Studies with ongoing pt accrual

Epoetin alfa Studies

ODAC 2004

EPO-ANE-3010

(Breast)

Other Studies

Aranesp Studies

outline70
Outline
  • Introduction
  • Regulatory History
  • Benefits vs Risks of ESAs
  • Safety signals leading to ODAC May 2004
  • ODAC 2004
  • Data from Recent Trials since ODAC 2004
  • “Meta Analyses” considerations
reasons against performing meta analysis
Reasons against performing Meta-Analysis
  • Can obscure safety signals from individual studies
  • Results depend on the studies included
    • Earlier meta-analyses suggested statistical significance on OS favoring ESAs
    • Later meta-analyses suggest statistical significance on OS favoring controls
  • Cumulative meta-analyses and retrospective meta-analyses have issues on appropriate allocation of alpha
  • Heterogeneous trials w/ variable quality, variable lengths of follow up, variable target Hgb, and heterogeneous tumor types
collective evidence
Collective Evidence
  • 6 studies have demonstrated inferior OS, LR PFS, or locoregional control for the ESA-containing arm
  • No studies that FDA has knowledge of have demonstrated superior OS or PFS for an ESA-containing arm
summary of hazards ratios for overall survival

Summary of Hazards Ratios for Overall Survival

1.00

Worse for Control

Worse for ESA

risks in patients without cancer
↑ Risks in patients without cancer
  • CHOIR
    • 1432 anemic CRF pts not on dialysis assigned to ESA targeting Hgb 13.5 vs 11.3
    • Increased CV events (Death, MI, CVA, CHF hospitalization) for Hgb 13.5 group (HR 1.3, 95% CI:1.0, 1.7, p=0.03).
  • Normal Hematocrit Study
    • 1265 hemodialysis pts w/clinically evident CV history (Ischemic heart dz or CHF) randomized to ESA targeting Hct 42 ± 3% vs 30 ± 3%
    • Increased mortality for Hct 42 group (35% v 29%)
tve in pts without cancer
↑ TVE in pts without cancer
  • SPINE
    • 681 patients undergoing major elective spinal surgery randomized to peri-operative ESA vs transfusion support
    • Primary endpoint: incidence of DVT
    • ↑ DVTs in patients receiving ESA (4.7% vs. 2.1%)
recent esa specific triggers for fda actions
Recent ESA-specific Triggersfor FDA Actions
  • November 2006 – CHOIR
  • December 2006 – DAHANCA (Head/Neck)
  • January 2007 - Anemia of Cancer
  • February 2007 - EPO CAN-20 (NSCLC), SPINE
  • April 2007 - Lymphoid Ca
fda actions
FDA Actions
  • FDA communication activities include:
    • Black Box Warning
    • Revised prescribing information
    • Public Health Advisories
    • Press Releases
    • Healthcare professional sheets
    • Medwatch Safety Alerts
    • E-mailed burst communications to healthcare professional societies
black box warning
Black Box Warning
  • Use lowest dose of ESAs that will gradually increase Hgb concentration to lowest level sufficient to avoid RBC transfusion
  • ESAs ↑ risk for death & for serious CV events when administered to target Hgb > 12
  • In pts w/cancer: use of ESAs
    • ↓ TTP w/advanced H&N Ca on RT when target Hgb>12, ↓ OS
    • ↑ deaths attributed to dz progression @ 4 months w/ Stg 4 Breast Ca on chemo when target Hgb>12
    • ↑ risk of death when target Hgb> 12 w/ active malignant disease receiving neither chemo nor RT
  • Surgery pts: ↑ incidence of DVT documented in pts on ESAs who were not receiving anticoagulation. Antithrombotic prophylaxis should be strongly considered when ESAs are used to ↓ allogeneic RBC transfusions
summary
Summary
  • 5 studies w/evidence of ↑ tumor promotion or ↓ survival with excessive target Hgb
    • BEST (Breast)*
    • ENHANCE (Head/Neck)
    • DAHANCA (Head/Neck)
    • 161 (Lymphoid Ca)*
    • CAN-20 (NSCLC)
  • 1 study w/evidence of ↓ survival with target Hgb consistent w/prior label (<13 g/dL)
    • 103 (Anemia of Cancer) (Many tumor types)

* = pts receiving chemo

summary81
Summary
  • A difference in OS was not observed in 2 trials in SCLC
    • Results in SCLC unlikely to be applicable to other tumor types
    • Both trials used ESAs to target Hgb > current or previous recommendations
summary82
Summary
  • EPO-ANE-3010 (Breast Ca)
    • Close to ideal in design
    • Uses US-labeled epoetin dose
    • Proposed at ODAC 2004 as capable of addressing tumor promotion risks
    • The only trial that adequately addresses TVE risk
    • Trial not accruing
  • 3 studies continue to accrue pts
    • Only EPO-ANE-3010 designed close to ideal
summary83
Summary
  • 12 studies presented at ODAC 2004 by J&J and Amgen as capable of addressing ESA tumor promotion risks.
    • 10 of these 12 studies are not adequately designed with respect to ODAC 04’s recommendations
  • Primary data from 5 completed epoetin studies with no reported safety signals not submitted to FDA.
    • These studies finished accrual as long as 6 years ago
conclusions
Conclusions
  • Efficacy of ESAs: ↓ RBC transfusions
  • Post-approval studies: ↓ OS, ↓ locoregional control, ↑ TVE risk
  • ESAs do NOT ↑ survival, and may ↑ tumor growth
  • Since 1993: ↓ RBC transfusion infectious risk vs ↑ ESA risk
  • Reconsideration of risk:benefit ratio of ESAs
  • No completed or ongoing trial has addressed safety issues of ESAs in cancer pts w/chemo associated anemia using currently approved dosing regimens in a generalizable tumor type